JP2008156297A - Serotonin 2b and/or 2c receptor antagonist - Google Patents
Serotonin 2b and/or 2c receptor antagonist Download PDFInfo
- Publication number
- JP2008156297A JP2008156297A JP2006348101A JP2006348101A JP2008156297A JP 2008156297 A JP2008156297 A JP 2008156297A JP 2006348101 A JP2006348101 A JP 2006348101A JP 2006348101 A JP2006348101 A JP 2006348101A JP 2008156297 A JP2008156297 A JP 2008156297A
- Authority
- JP
- Japan
- Prior art keywords
- serotonin receptor
- serotonin
- antagonist
- disorders
- compound represented
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- MRIAQLRQZPPODS-UHFFFAOYSA-N COc(ccc(C(Oc(c1c(c(OC)c2OC)OC)c2OC)=CC1=O)c1)c1OC Chemical compound COc(ccc(C(Oc(c1c(c(OC)c2OC)OC)c2OC)=CC1=O)c1)c1OC MRIAQLRQZPPODS-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明はセロトニン２Ｂおよび／または２Ｃ受容体拮抗剤に関し、更に詳細には、摂食障害などのセロトニン２Ｂおよび／または２Ｃ受容体に関連する疾患の予防・治療効果を有するセロトニン２Ｂおよび／または２Ｃ受容体拮抗剤に関する。 The present invention relates to a serotonin 2B and / or 2C receptor antagonist, and more specifically, serotonin 2B and / or 2C having a prophylactic / therapeutic effect on diseases related to serotonin 2B and / or 2C receptors such as eating disorders. It relates to a receptor antagonist.
セロトニンは５−ヒドロキシトリプタミン（５−ＨＴ）とも呼ばれる生理活性アミンの一つであり、１種のホルモンとして機能し、平滑筋の収縮を制御している。また、セロトニンは神経伝達物質として、生体内において受容体を介して様々な生理作用を示す。 Serotonin is one of bioactive amines also called 5-hydroxytryptamine (5-HT), functions as a kind of hormone, and controls the contraction of smooth muscle. In addition, serotonin exhibits various physiological actions as a neurotransmitter in vivo via a receptor.
セロトニン受容体には、これまで多数のサブタイプが報告されており、その中のいくつかについて生体内分布や機能との関連が明らかとなってきている。例えば、サブタイプ３は抹消神経、最後野等に存在し、摂食や血圧・呼吸反射等に関与しており、サブタイプ４は、海馬、腸神経叢、心臓などに存在し、胃液分泌および蠕動運動を亢進させたり、心臓では心収縮力と拍動数を増加させる機能を有する。 Many serotonin receptors have been reported so far, and some of them have been revealed to be related to biodistribution and function. For example, subtype 3 is present in the peripheral nerve, the last cortex, etc., and is involved in feeding, blood pressure, respiratory reflex, etc., and subtype 4 is present in the hippocampus, intestinal plexus, heart, etc. It has the function of enhancing peristaltic movement and increasing the contractile force and the number of beats in the heart.
一方セロトニン受容体２は、さらにサブタイプ２Ａ〜２Ｃに分類される。これらのうちサブタイプ２Ｂは主に胃など末梢器官に存在し胃底部平滑筋収縮などに関与しており、サブタイプ２Ｃは主に脳など中枢神経系に存在し脳脊髄液産生調節機能などに関与するものであるが、いずれも様々な疾患に関連することが知られている。例えば、サブタイプ２Ｃには、特に肥満などの摂食障害、記憶障害、精神分裂病、気分障害、不安障害、疼痛、性的機能不全、泌尿器疾患およびうつ病との関連が報告されている（特許文献１）。 On the other hand, serotonin receptor 2 is further classified into subtypes 2A to 2C. Of these, subtype 2B is mainly present in peripheral organs such as the stomach and is involved in gastric fundus smooth muscle contraction, etc., and subtype 2C is mainly present in the central nervous system such as the brain and functions such as cerebrospinal fluid production regulation. All of which are known to be associated with various diseases. For example, subtype 2C has been reported to be associated with eating disorders such as obesity, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, sexual dysfunction, urinary diseases and depression in particular ( Patent Document 1).
また、サブタイプ２Ｂには、偏頭痛、高血圧、胃腸管障害、再狭窄、喘息、閉塞性気道疾患、肺気管支異形成、前立腺肥大、持続勃起症、アレルギー喘息、過敏性大腸症候群、下部食道括約筋過緊張、消化管運動異常、良性前立腺肥大などの疾患との関連が報告されている（特許文献２および３）。 Subtype 2B includes migraine, hypertension, gastrointestinal tract disorder, restenosis, asthma, obstructive airway disease, pulmonary bronchial dysplasia, prostatic hypertrophy, persistent erectile dysfunction, allergic asthma, irritable bowel syndrome, lower esophageal sphincter The relationship with diseases such as hypertony, gastrointestinal motility abnormalities, and benign prostatic hypertrophy has been reported (Patent Documents 2 and 3).
このようにセロトニン受容体２Ｂ、２Ｃが関連する疾患として種々のものがあり、生体内においてこれらのセロトニン受容体との結合を阻害する物質は、そのような疾患の予防薬や治療薬として有用である。また、セロトニン受容体３または４の拮抗剤は既に開発されているが、２Ｂ、２Ｃの拮抗剤はいまだ有効な薬剤が開発されていない。 As described above, there are various diseases associated with serotonin receptors 2B and 2C, and substances that inhibit the binding to these serotonin receptors in vivo are useful as preventive or therapeutic agents for such diseases. is there. In addition, an antagonist of serotonin receptor 3 or 4 has already been developed, but an effective drug has not yet been developed for antagonists of 2B and 2C.
従って本発明は、有効にセロトニン受容体、特にサブタイプ２Ｂや２Ｃへの結合阻害作用を有する物質を見出し、これを利用するセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤を提供することをその課題とする。 Accordingly, it is an object of the present invention to provide a serotonin receptor 2B and / or 2C antagonist that effectively finds a substance having an inhibitory action on binding to serotonin receptors, particularly subtypes 2B and 2C. To do.
本発明者らは、上記課題を解決すべく、セロトニン受容体拮抗作用を有する物質を鋭意検索していたところ、特定の構造式で表される化合物がセロトニン受容体２Ｂや２Ｃに対して優れた拮抗作用を有することを見出し、本発明を完成した。 In order to solve the above-mentioned problems, the present inventors have eagerly searched for a substance having a serotonin receptor antagonistic action, and the compound represented by a specific structural formula is superior to serotonin receptors 2B and 2C. The present invention was completed by finding an antagonistic action.
すなわち本発明は、
下記式（１）ないし（４）、
The following formulas (1) to (4),
本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤に配合される式（１）ないし（４）の化合物は、セロトニン受容体サブタイプ２Ｂおよび／または２Ｃに対し優れた結合阻害作用を有するものである。従って、これらを有効成分とする本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤は、セロトニン受容体が関連する摂食障害などの疾患の治療に有効なものである。 The compounds of the formulas (1) to (4) blended in the serotonin receptor 2B and / or 2C antagonist of the present invention have an excellent binding inhibitory action on the serotonin receptor subtype 2B and / or 2C. is there. Therefore, the serotonin receptor 2B and / or 2C antagonist of the present invention containing these as active ingredients is effective for the treatment of diseases such as eating disorders associated with the serotonin receptor.
本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤において使用される有効成分の一つとしては、下記の一般式（１）で表される化合物が用いられる。 As one of the active ingredients used in the serotonin receptor 2B and / or 2C antagonist of the present invention, a compound represented by the following general formula (1) is used.
上記式（１）で表される化合物には、下記式（５）ないし（９）の化合物が含まれており、これらが好ましく用いられる。これらの化合物の慣用名は、それぞれ８−ギンゲロール、１０−ギンゲロール、８−ショーガオール、１０−ギンゲルジオン、１０−デヒドロギンゲルジオンである。 The compound represented by the above formula (1) includes compounds of the following formulas (5) to (9), and these are preferably used. Common names for these compounds are 8-Gingerol, 10-Gingerol, 8-Shogaol, 10-Gingergeldione, 10-DehydroGingerdione, respectively.
これらの化合物は、公知方法によって単離するか、または市販品を用いることができる。例えば、１０−ギンゲルジオンおよび１０−デヒドロギンゲルジオンは、Chem. Pharm. Bull., 40(2), P.389-391 (1992)やChem. Pharm. Bull., 30(2), P.754-757 (1982)に記載の分離精製方法によって得ることができる。また８−ギンゲロールおよび１０−ギンゲロールはクロマデックス・インク（ChromaDex,Inc）から、８−ショーガオールは和光純薬工業からそれぞれ市販されており、これを用いることができる。 These compounds can be isolated by known methods, or commercially available products can be used. For example, 10-gingerdione and 10-dehydrogingeredione are known as Chem. Pharm. Bull., 40 (2), P.389-391 (1992) and Chem. Pharm. Bull., 30 (2), P.754. -757 (1982). 8-Gingerol and 10-Gingerol are commercially available from Chromadex, Inc. and 8-Shogaol is commercially available from Wako Pure Chemical Industries, respectively.
また、本発明に用いる有効成分として下記一般式（２）で表される化合物を用いることもできる。 Moreover, the compound represented by following General formula (2) can also be used as an active ingredient used for this invention.
上記式（２）で表される化合物には、下記式（１０）ないし（１５）の化合物が含まれ、これらが好ましく用いられる。これらの化合物の慣用名はそれぞれ、タンゲレチン、３，３’，４’，５，６，７，８−ヘプタメトキシフラボン、ナリンゲシン、ノビレチン、リクイリチゲニン、ヘスペレチンである。 The compound represented by the above formula (2) includes compounds of the following formulas (10) to (15), and these are preferably used. Common names for these compounds are tangeretin, 3,3 ', 4', 5,6,7,8-heptamethoxyflavone, naringesin, nobiletin, liquiritigenin, hesperetin, respectively.
これらの化合物は公知の方法により単離または合成するか、あるいは市販品を用いることができる。例えば、タンゲレチン、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンおよびノビレチンは公知方法により分離精製して得ることができる（Chem. Pharm. Bull., 37(4), P.1092-1094 (1989)、Chem. Pharm. Bull., 35(7), P.3025-3028 (1987)）。 These compounds can be isolated or synthesized by known methods, or commercially available products can be used. For example, tangeretin, 3,3 ′, 4 ′, 5,6,7,8-heptamethoxyflavone and nobiletin can be obtained by separation and purification by known methods (Chem. Pharm. Bull., 37 (4), P.1092-1094 (1989), Chem. Pharm. Bull., 35 (7), P.3025-3028 (1987)).
一方、ナリンゲニンおよびヘスペレチンは公知方法により合成することができる（薬学雑誌、48(10), P.933-937 (1928)、薬学雑誌、48(10), P.938-941 (1928)）。またリクイリチゲニンは、クロマッデクス・インク（ChromaDex,Inc）から市販されているものを用いることができる。 On the other hand, naringenin and hesperetin can be synthesized by known methods (Pharmaceutical Journal, 48 (10), P.933-937 (1928), Pharmaceutical Journal, 48 (10), P.938-941 (1928)). As liquiritigenin, commercially available from Chromadex, Inc. can be used.
さらに、本発明に用いる有効成分として、下記式（３）で表されるグリシクマリンおよび式（４）で表されるイソリチリチゲニンを用いることができる。 Furthermore, glycycmarin represented by the following formula (3) and isolithyritigenin represented by the formula (4) can be used as active ingredients used in the present invention.
上記グリシクマリンは、例えばChem. Pharm. Bull., 36(6), P.2090-2097 (1988)に記載の方法で単離することができ、また、イソリチリチゲニンはシグマ（Sigma）社から市販されているので、これを用いることができる。 The glycycumarin can be isolated by the method described in, for example, Chem. Pharm. Bull., 36 (6), P.2090-2097 (1988), and isolithyritigenin is produced by Sigma. Can be used since it is commercially available.
本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤は、上記した化合物を有効成分とし、他の医薬用担体と適宜混合し、これを経口剤あるいは非経口剤として製剤化することにより製造することができる。 The serotonin receptor 2B and / or 2C antagonist of the present invention is produced by using the above-mentioned compound as an active ingredient, mixing it with other pharmaceutical carriers as appropriate, and formulating it as an oral or parenteral preparation. Can do.
経口剤としては、粉剤、散剤、顆粒剤、錠剤、カプセル剤、軟カプセル剤、液剤等とすることができ、これに応じた医薬用担体、例えば、デンプン、乳糖、白糖、マンニット、カルボキシメチルセルロース、コーンスターチ、無機塩等を利用することができる。また、経口剤の調製にあたっては、更に結合剤、崩壊剤、界面活性剤、滑沢剤、流動性促進剤、矯味剤、着色剤、香料等を配合することができる。 Oral preparations can be powders, powders, granules, tablets, capsules, soft capsules, liquids, etc., and pharmaceutical carriers corresponding thereto, such as starch, lactose, sucrose, mannitol, carboxymethylcellulose Corn starch, inorganic salt, etc. can be used. In preparation of the oral preparation, a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a corrigent, a colorant, a fragrance and the like can be further blended.
また、非経口剤も常法に従って製造され、希釈剤として一般に注射用蒸留水、生理食塩水、ブドウ糖水溶液、注射用植物油、ゴマ油、ラッカセイ油、ダイズ油、トウモロコシ油、プロピレングリコール、ポリエチレングリコール等を用いることができる。更に、必要に応じて、殺菌剤、防腐剤、安定剤を加えてもよい。 Parenteral preparations are also produced according to conventional methods. As diluents, distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol and the like are generally used. Can be used. Furthermore, you may add a bactericidal agent, antiseptic | preservative, and a stabilizer as needed.
更に、この非経口剤は安定性の点から、バイアル等に充填後冷凍し、通常の凍結乾燥技術により水分を除去し、使用直前に凍結乾燥物から液剤を再調製することもできる。更にまた、必要に応じて適宜、等張化剤、安定剤、防腐剤、無痛化剤等を加えてもよい。その他の非経口剤としては、外用液剤、軟膏等の塗布剤、直腸内投与のための坐剤等が挙げられ、これらは何れも常法に従って製造される。 Furthermore, from the viewpoint of stability, this parenteral preparation can be frozen after filling into a vial or the like, the water can be removed by a normal freeze-drying technique, and the liquid preparation can be re-prepared from the freeze-dried product immediately before use. Furthermore, tonicity agents, stabilizers, preservatives, soothing agents and the like may be added as necessary. Examples of other parenteral preparations include coating solutions for external use, ointments and the like, suppositories for rectal administration, etc., all of which are manufactured according to conventional methods.
本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤において、有効成分である化合物の配合量は、化合物の種類、対象疾患、疾患程度、患者年齢等によっても相違するが、例えば、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンを用いる場合は、大人一人当たり一日量として、１ｍｇないし１ｇ程度であり、１００ｍｇないし５００ｍｇとすることが好ましい。他の化合物を用いる場合も、大人一人当たり一日量としては、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンと同程度とすることが好ましい。 In the serotonin receptor 2B and / or 2C antagonist of the present invention, the compounding amount of the compound that is an active ingredient varies depending on the type of compound, target disease, disease level, patient age, etc., for example, 3, 3 ′ , 4 ′, 5,6,7,8-heptamethoxyflavone, the daily dose per adult is about 1 mg to 1 g, preferably 100 mg to 500 mg. Even when other compounds are used, the daily dose per adult is preferably about the same as 3,3 ', 4', 5,6,7,8-heptamethoxyflavone.
以上のようにして得られる本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤は、セロトニン受容体２Ｂ、２Ｃが関連する種々の疾患、例えば、摂食障害、記憶障害、精神分裂病、気分障害、不安障害、疼痛、性的機能不全、泌尿器疾患およびうつ病などの主に２Ｃと関連する疾患や、偏頭痛、高血圧、胃腸管障害、再狭窄、喘息、閉塞性気道疾患、肺気管支異形成、前立腺肥大、持続勃起症、アレルギー喘息、過敏性大腸症候群、下部食道括約筋過緊張、消化管運動異常および良性前立腺肥大などの主に２Ｂが関連する疾患の予防・治療に有用である。 The serotonin receptor 2B and / or 2C antagonist of the present invention obtained as described above is used in various diseases associated with serotonin receptors 2B and 2C, such as eating disorders, memory disorders, schizophrenia, and mood disorders. , Anxiety disorder, pain, sexual dysfunction, urinary disease and depression, mainly related to 2C, migraine, hypertension, gastrointestinal disorders, restenosis, asthma, obstructive airway disease, pulmonary bronchial dysplasia , Prostatic hypertrophy, persistent erectile dysfunction, allergic asthma, irritable bowel syndrome, lower esophageal sphincter hypertonia, gastrointestinal motility abnormalities, and benign prostatic hypertrophy are useful for the prevention and treatment of 2B-related diseases.
また、本発明に用いられる化合物のうち、８−ギンゲロール、タンゲレチン、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンおよびノビレチンの４種類の化合物は、セロトニン受容体２Ｂに選択的に作用するが、２Ｂは主に末梢器官に存在し、２Ｃと比較して脳などの中枢神経には少ないため、中枢神経系への影響等の面で有利に利用できるものである。 Among the compounds used in the present invention, four types of compounds such as 8-gingerol, tangeretin, 3,3 ′, 4 ′, 5,6,7,8-heptamethoxyflavone and nobiletin are present in serotonin receptor 2B. Although it acts selectively, 2B is mainly present in peripheral organs and is less in the central nervous system such as the brain than 2C, and thus can be used advantageously in terms of effects on the central nervous system.
次に実施例を挙げ、本発明を更に詳しく説明するが、本発明はこれら実施例に何ら制約されるものではない。 EXAMPLES Next, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples.
実 施 例 １
セロトニン受容体２Ｂ結合阻害試験：
セロトニン受容体２Ｂのリガンド［３Ｈ］ＬＳＤ（Lysergic acid diethylamide）の特異的結合に対する阻害作用を調べた。
Example 1
Serotonin receptor 2B binding inhibition test:
The inhibitory effect on specific binding of the ligand [ 3 H] LSD (Lysergic acid diethylamide) of serotonin receptor 2B was examined.
（１）被験物質
次の１３種類の化合物を被験物質として用いた。
８−ギンゲロール、１０−ギンゲロール、８−ショーガオール、１０−ギンゲルジオン、１０−デヒドロギンゲルジオン、タンゲレチン、３，３’，４’，５，６，７，８−ヘプタメトキシフラボン、ナリンゲニン、ノギレチン、リクイリチゲニン、ヘスペレチン、グリシクマリン、イソリチリチゲニン
(1) Test substances The following 13 kinds of compounds were used as test substances.
8-gingerol, 10-gingerol, 8-shogaol, 10-gingerdione, 10-dehydrogingeredione, tangeretin, 3,3 ′, 4 ′, 5,6,7,8-heptamethoxyflavone, naringenin, nogiletin, Liquiritigenin, hesperetin, glycicmarin, isolicyritigenin
（２）受容体結合阻害試験
Ｔｒｉｓ−ＨＣＩ緩衝液（ｐＨ７．７に、リコンビナントセロトニン２Ｂ受容体３０μｇ、１．２ｎＭの［３Ｈ］ＬＳＤおよび被験物質を加え３７℃、６０分間インキュベーションした後、ガラス繊維フィルターにより濾過した。フィルターを洗浄し、液体シンチレーションカウンターで放射活性を測定した。この結合量から１０μＭセロトニン存在下の非特異的結合量を差し引いて［３Ｈ］ＬＳＤとの特異的結合量を求めた。この特異的結合を５０％抑制するために必要な被験物質の量をＩＣ50値とし、非線形最小二乗法により求めた。その結果を表１に示す。
(2) Receptor binding inhibition test Tris-HCI buffer (pH 7.7, 30 μg of recombinant serotonin 2B receptor, 1.2 nM [ 3 H] LSD and a test substance were added and incubated at 37 ° C. for 60 minutes, and then glass was added. The filter was washed and the radioactivity was measured with a liquid scintillation counter, and the amount of specific binding to [ 3 H] LSD was subtracted from the amount of non-specific binding in the presence of 10 μM serotonin. The amount of the test substance required to suppress this specific binding by 50% was determined as an IC 50 value by the non-linear least square method, and the results are shown in Table 1.
実 施 例 ２
セロトニン受容体２Ｃ結合阻害試験：
セロトニン受容体２Ｃのリガンド［３Ｈ］メスレルギンの特異的結合に対する阻害作用を調べた。
Example 2
Serotonin receptor 2C binding inhibition test:
The inhibitory effect of serotonin receptor 2C on the specific binding of the ligand [ 3 H] meslergin was examined.
（１）被験物質
実施例１で用いた化合物のうち、リクイリチゲニンを除いた１２種類の化合物を用いた。
（２）受容体結合阻害試験
Ｔｒｉｓ−ＨＣＩ緩衝液（ｐＨ７．７） に、リコンビナントセロトニン２Ｃ受容体３.２μｇ、１．０ｎＭの［３Ｈ］メスレルギンおよび被験物質を加え２５℃、６０分間インキュベーションした後、ガラス繊維フィルターにより濾過した。フィルターを洗浄し、液体シンチレーションカウンターで放射活性を測定した。この結合量から１μＭミアンセリン存在下の非特異的結合量を差し引いて［３Ｈ］メスレルギンとの特異的結合量を求めた。それぞれの被験物質について実施例１と同様にしてＩＣ50値を求めた。結果を表１に示す。
(1) Test substance Among the compounds used in Example 1, 12 kinds of compounds excluding liquiritigenin were used.
(2) Receptor binding inhibition test To Tris-HCI buffer (pH 7.7), 3.2 μg of recombinant serotonin 2C receptor, 1.0 nM [ 3 H] meslergin and a test substance were added and incubated at 25 ° C. for 60 minutes. Then, it filtered with the glass fiber filter. The filter was washed and the radioactivity was measured with a liquid scintillation counter. The amount of specific binding to [ 3 H] meselgin was determined by subtracting the amount of non-specific binding in the presence of 1 μM mianserin from this amount of binding. IC 50 values were determined for each test substance in the same manner as in Example 1. The results are shown in Table 1.
実 施 例 ３
セロトニン受容体３結合阻害試験：
セロトニン受容体３のリガンド［３Ｈ］ＧＲ−６５６３０（３‐（５‐メチル‐１Ｈ‐イミダゾール‐４‐イル）‐１‐（１‐メチル‐１Ｈ‐インドール‐２‐イル）‐１‐プロパノン）の特異的結合に対する阻害作用を調べた。
Example 3
Serotonin receptor 3 binding inhibition test:
Serotonin receptor 3 ligand [ 3 H] GR-65630 (3- (5-methyl-1H-imidazol-4-yl) -1- (1-methyl-1H-indol-2-yl) -1-propanone) The inhibitory effect on the specific binding of was investigated.
（１）被験物質
実施例１で用いた化合物のうち、グリシクマリン、イソリクイリチゲニン、ナリンゲリンおよびリクイリチゲニンを除いた９種類の化合物を用いた。
(1) Test substance Among the compounds used in Example 1, nine types of compounds were used except for glycicmarin, isoliquiritigenin, naringerin and liquiritigenin.
（２）受容体結合阻害試験
Ｔｒｉｓ−ＨＣＩ緩衝液（ｐＨ７．５） に、ヒトリコンビナントセロトニン３受容体３.２μｇ、０．６９ｎＭの［３Ｈ］ＧＲ−６５６３０および被験物質を加え２５℃、６０分間インキュベーションした後、ガラス繊維フィルターにより濾過した。フィルターを洗浄し、液体シンチレーションカウンターで放射活性を測定した。この結合量から１μＭ ＭＤＬ−７２２２（３，５‐ジクロロ安息香酸（１β，５β）‐８‐メチル‐８‐アザビシクロ［３．２．１］オクタン‐３α‐イル）存在下の非特異的結合量を差し引いて［３Ｈ］ＧＲ−６５６３０との特異的結合量を求めた。それぞれの被験物質について、実施例１と同様にしてＩＣ50値を求めた。結果を表１に示す。
(2) Receptor binding inhibition test To Tris-HCI buffer (pH 7.5), 3.2 μg of human recombinant serotonin 3 receptor, 0.69 nM [ 3 H] GR-65630 and a test substance were added, and the test was performed at 25 ° C., 60 ° C. After a minute incubation, it was filtered through a glass fiber filter. The filter was washed and the radioactivity was measured with a liquid scintillation counter. From this amount of binding, the amount of non-specific binding in the presence of 1 μM MDL-7222 (3,5-dichlorobenzoic acid (1β, 5β) -8-methyl-8-azabicyclo [3.2.1] octane-3α-yl) Was subtracted to determine the amount of specific binding with [ 3 H] GR-65630. IC 50 values were determined for each test substance in the same manner as in Example 1. The results are shown in Table 1.
実 施 例 ４
セロトニン受容体４結合阻害試験：
セロトニン受容体４のアンタゴニスト［３Ｈ］ＧＲ−１１３８０８（１−（２−メチルエチルスルホニルアミノエチル）−４−ピペリジニルメチル １−メチルー１Ｈ−インドール−３−カルボキシレート）の特異的結合に対する阻害作用を調べた。
Example 4
Serotonin receptor 4 binding inhibition test:
Inhibition of the specific binding of serotonin receptor 4 antagonist [ 3 H] GR-113808 (1- (2-methylethylsulfonylaminoethyl) -4-piperidinylmethyl 1-methyl-1H-indole-3-carboxylate) The effect was investigated.
（１）被験物質
実施例１で用いた化合物のうち、グリシクマリン、イソリクイリチゲニンおよびヘスペレチン（計３種類の化合物）を用いた。
(1) Test substance Among the compounds used in Example 1, glycicmarin, isoliquiritigenin and hesperetin (a total of three kinds of compounds) were used.
（２）膜の調製
ハートレイ系モルモット（体重２５０±２０ｇ）を用い、脳線条体を採取した。組織をＴｒｉｓ−ＨＣＩ緩衝液（ｐＨ７．４）でホモジナイスした後、遠心分離し、膜分画（ペレット部）を得た。
(2) Membrane preparation Brain striatum was collected using Hartley guinea pigs (body weight 250 ± 20 g). The tissue was homogenized with Tris-HCI buffer (pH 7.4) and then centrifuged to obtain a membrane fraction (pellet part).
（３）受容体結合阻害試験
Ｔｒｉｓ−ＨＣＩ緩衝液（ｐＨ７．４）に、膜画分１２．５ｍｇ、０．７ｎＭの［３Ｈ］ＧＲ−１１３８０８および被験物質を加え２５℃、６０分間インキュベーションした後、ガラス繊維フィルターにより濾過した。フィルターを洗浄し、液体シンチレーションカウンターで放射活性を測定した。この結合量から３０μＭ セロトニン存在下の非特異的結合量を差し引いて［３Ｈ］ＧＲ−１１３８０８との特異的結合量を求めた。それぞれの被験物質について、実施例１と同様にしてＩＣ50値を求めた。結果を表１に示す。
(3) Receptor binding inhibition test To Tris-HCI buffer (pH 7.4), 12.5 mg of a membrane fraction, 0.7 nM [ 3 H] GR-113808 and a test substance were added and incubated at 25 ° C. for 60 minutes. Then, it filtered with the glass fiber filter. The filter was washed and the radioactivity was measured with a liquid scintillation counter. The amount of specific binding to [ 3 H] GR-113808 was determined by subtracting the amount of non-specific binding in the presence of 30 μM serotonin from this amount of binding. IC 50 values were determined for each test substance in the same manner as in Example 1. The results are shown in Table 1.
いずれの化合物もセロトニン受容体２Ｂに対して結合阻害活性を示した。このうち、８−ギンゲロール、タンゲレチン、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンおよびノビレチンは、２Ｂに対して選択的に結合阻害活性を示し、その他の化合物は２Ｂおよび２Ｃのいずれに対しても阻害活性を示した。またセロトニン受容体３に対しては、試験したいずれの化合物も阻害活性は低く、２Ｂおよび／または２Ｃ選択性を示した。さらに、イソリクイリチゲニンおよびヘスペレチンはセロトニン受容体４に対しても阻害活性は低く２Ｂおよび２Ｃ選択性を示した。セロトニン受容体３、４、２Ｂおよび２Ｃはそれぞれ種々の生理活性を有するため、特定のサブタイプに選択性を有することは副作用の点で有利である。 All the compounds showed binding inhibitory activity against serotonin receptor 2B. Among these, 8-gingerol, tangeretin, 3,3 ′, 4 ′, 5,6,7,8-heptamethoxyflavone and nobiletin selectively show binding inhibitory activity against 2B, and the other compounds are 2B. Inhibitory activity was exhibited against both of 2C and 2C. Further, for the serotonin receptor 3, all the tested compounds showed low inhibitory activity and showed 2B and / or 2C selectivity. Furthermore, isoliquiritigenin and hesperetin had low inhibitory activity against serotonin receptor 4 and showed 2B and 2C selectivity. Since serotonin receptors 3, 4, 2B and 2C each have various physiological activities, it is advantageous in terms of side effects to have selectivity for a specific subtype.
製 剤 例 １
３，３’，４’，５，６，７，８−ヘプタメトキシフラボン１００ｇを乳糖２７０ｇ、微結晶セルロース１２０ｇ、およびステアリン酸マグネシウム１０ｇと混合し、この混合物を単発式打錠機にて打錠して直径９mm、重量２５０mgの錠剤を製造した。
Product example 1
3,3 ′, 4 ′, 5,6,7,8-Heptamethoxyflavone 100 g was mixed with 270 g of lactose, 120 g of microcrystalline cellulose and 10 g of magnesium stearate, and this mixture was tableted with a single tablet press. Thus, a tablet having a diameter of 9 mm and a weight of 250 mg was produced.
本錠剤１錠は、３，３’，４’，５，６，７，８−ヘプタメトキシフラボンを５０mg含有し、症状にあわせて１日３〜１０錠を数回に分けて服用するものであるする。 This tablet contains 50 mg of 3,3 ′, 4 ′, 5,6,7,8-heptamethoxyflavone, and 3 to 10 tablets a day according to the symptoms. There is.
製 剤 例 ２
ノビレチン５０ｇをトウモロコシデンプン９５０ｇと混合し、水を加えて練合し、１ｍｍ×１ｍｍの網目を有するスクリーンにて造粒、乾燥して顆粒剤とした。
Product example 2
50 g of nobiletin was mixed with 950 g of corn starch, kneaded with water, granulated on a screen having a 1 mm × 1 mm network, and dried to give granules.
本顆粒剤１ｇは、ノビレチンを５０mg含有し、症状にあわせて１日２〜６ｇを数回に分けて服用するものである。 1 g of this granule contains 50 mg of nobiletin and is taken 2 to 6 g per day according to symptoms.
製 剤 例 ３
タンゲレチン１００ｇを乳糖２１０ｇ、でんぷん１２０ｇ、滑石５０ｇ、ステアリン酸マグネシウム２０ｇと混合し、２５０mgずつ硬カプセルに充填してカプセル剤を製造した。
Product example 3
A capsule was prepared by mixing 100 g of tangeretin with 210 g of lactose, 120 g of starch, 50 g of talc and 20 g of magnesium stearate and filling each 250 mg into a hard capsule.
本カプセル剤１カプセルは、タンゲレチンを５０mg含有し、症状にあわせて１日３〜１０カプセルを数回にわけて服用するものである。 One capsule contains 50 mg of tangeretin, and 3 to 10 capsules per day according to the symptoms.
本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤は、セロトニン受容体サブタイプのうち、２Ｂおよび／または２Ｃに対し優れた結合阻害作用を有するものである。 The serotonin receptor 2B and / or 2C antagonist of the present invention has an excellent binding inhibitory effect on 2B and / or 2C among the serotonin receptor subtypes.
従って本発明のセロトニン受容体２Ｂおよび／または２Ｃ拮抗剤は、セロトニン受容体２Ｂ、２Ｃが関連する種々の疾患、例えば、摂食障害、記憶障害、精神分裂病、気分障害、不安障害、疼痛、性的機能不全、泌尿器疾患およびうつ病などの主に２Ｃと関連する疾患や、偏頭痛、高血圧、胃腸管障害、再狭窄、喘息、閉塞性気道疾患、肺気管支異形成、前立腺肥大、持続勃起症、アレルギー喘息、過敏性大腸症候群、下部食道括約筋過緊張、消化管運動異常および良性前立腺肥大などの主に２Ｂが関連する疾患の予防・治療に有効なものである。
以 上
Accordingly, the serotonin receptor 2B and / or 2C antagonists of the present invention can be used in various diseases associated with serotonin receptors 2B and 2C, such as eating disorders, memory disorders, schizophrenia, mood disorders, anxiety disorders, pain, Diseases mainly related to 2C such as sexual dysfunction, urological diseases and depression, migraine, hypertension, gastrointestinal tract disorder, restenosis, asthma, obstructive airway disease, pulmonary bronchial dysplasia, prostate enlargement, persistent erection It is effective for the prevention and treatment of diseases mainly related to 2B, such as hypertension, allergic asthma, irritable bowel syndrome, lower esophageal sphincter hypertonia, gastrointestinal motility abnormality, and benign prostatic hypertrophy.
more than
Claims (6)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006348101A JP2008156297A (en) | 2006-12-25 | 2006-12-25 | Serotonin 2b and/or 2c receptor antagonist |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2006348101A JP2008156297A (en) | 2006-12-25 | 2006-12-25 | Serotonin 2b and/or 2c receptor antagonist |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JP2008156297A true JP2008156297A (en) | 2008-07-10 |
Family
ID=39657631
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2006348101A Pending JP2008156297A (en) | 2006-12-25 | 2006-12-25 | Serotonin 2b and/or 2c receptor antagonist |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2008156297A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2323649A4 (en) * | 2008-07-25 | 2011-09-07 | Univ Emory | Treating various disorders with 7,8-dihydroxyflavone and derivatives thereof |
| CN102215857A (en) * | 2008-11-19 | 2011-10-12 | 庆熙大学校产学协力团 | Pharmaceutical composition containing ginger extract or shogaol |
| JP2012062261A (en) * | 2010-09-15 | 2012-03-29 | Maruzen Pharmaceut Co Ltd | Composition for improving mood disorders |
| CN102552242A (en) * | 2012-01-18 | 2012-07-11 | 李康 | Application of nobiletin to preparation of medicament for treating allelgic asthma |
| JP2013071928A (en) * | 2011-09-29 | 2013-04-22 | Yoshiko Furukawa | Composition for treatment of cranial nerve disease, prevention of cranial nerve disease or improvement in brain function |
| KR101369882B1 (en) * | 2012-01-17 | 2014-03-26 | 한국화학연구원 | Pharmaceutical composition for the prevention or treatment of asthma comprising (4-hydroxy-3-methoxyphenyl)butenone derivative or a pharmaceutically acceptable salt thereof as an active ingredient |
| WO2016016153A1 (en) * | 2014-07-30 | 2016-02-04 | Symrise Ag | Hydroxyflavanones as appetite stimulants |
| US20170029399A1 (en) * | 2014-01-28 | 2017-02-02 | Virginia Commonwealth University | 2-substituted-5-hydroxy-4h-chromen-4-ones as novel ligands for the serotonin receptor 2b (5-ht2b) |
| JPWO2016075960A1 (en) * | 2014-11-12 | 2017-08-17 | 株式会社 沖縄リサーチセンター | Pharmaceutical composition for preventing or ameliorating urination disorder, antagonist for urination disorder-related receptor or method for preventing or ameliorating urination disorder using the pharmaceutical composition or antagonist |
| CN114984000A (en) * | 2022-06-14 | 2022-09-02 | 中国科学院昆明动物研究所 | Application of toddaline and/or glycycoumarin in preparing medicine for improving resistance to pain |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000512621A (en) * | 1996-04-15 | 2000-09-26 | ファーマプリント，インコーポレーテッド | Pharmaceutical grade botanicals |
| JP2001314169A (en) * | 2000-05-09 | 2001-11-13 | Sakamoto Yakusoen:Kk | Kintoki ginger-based health food |
| JP2002047195A (en) * | 2000-07-12 | 2002-02-12 | Pharmaceutical Industry Technology & Development Center | Method for producing extract containing active ingredient of ginger and pharmaceutical composition comprising the same extract |
| WO2005080322A1 (en) * | 2004-02-20 | 2005-09-01 | Astellas Pharma Inc. | Fluorene derivative |
| JP2005325093A (en) * | 2004-05-12 | 2005-11-24 | Fumiko Naka | Method for producing total lotion composed of ginger |
| JP2005538065A (en) * | 2002-06-17 | 2005-12-15 | フイラデルフイア・ヘルス・アンド・エデユケーシヨン・コーポレーシヨン | Immunoregulation of serotonin family receptors and blood-brain barrier and effects on cellular processes |
| JP2007063138A (en) * | 2005-08-29 | 2007-03-15 | Daicho Kikaku:Kk | Therapeutic agent for irritable colitis, therapeutic agent for ulcerative colitis, therapeutic agent for crohn's disease, therapeutic agent for regional ileitis and therapeutic agent for sterility |
| JP2007246470A (en) * | 2006-03-17 | 2007-09-27 | Daicho Kikaku:Kk | New medicine |
-
2006
- 2006-12-25 JP JP2006348101A patent/JP2008156297A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000512621A (en) * | 1996-04-15 | 2000-09-26 | ファーマプリント，インコーポレーテッド | Pharmaceutical grade botanicals |
| JP2001314169A (en) * | 2000-05-09 | 2001-11-13 | Sakamoto Yakusoen:Kk | Kintoki ginger-based health food |
| JP2002047195A (en) * | 2000-07-12 | 2002-02-12 | Pharmaceutical Industry Technology & Development Center | Method for producing extract containing active ingredient of ginger and pharmaceutical composition comprising the same extract |
| JP2005538065A (en) * | 2002-06-17 | 2005-12-15 | フイラデルフイア・ヘルス・アンド・エデユケーシヨン・コーポレーシヨン | Immunoregulation of serotonin family receptors and blood-brain barrier and effects on cellular processes |
| WO2005080322A1 (en) * | 2004-02-20 | 2005-09-01 | Astellas Pharma Inc. | Fluorene derivative |
| JP2005325093A (en) * | 2004-05-12 | 2005-11-24 | Fumiko Naka | Method for producing total lotion composed of ginger |
| JP2007063138A (en) * | 2005-08-29 | 2007-03-15 | Daicho Kikaku:Kk | Therapeutic agent for irritable colitis, therapeutic agent for ulcerative colitis, therapeutic agent for crohn's disease, therapeutic agent for regional ileitis and therapeutic agent for sterility |
| JP2007246470A (en) * | 2006-03-17 | 2007-09-27 | Daicho Kikaku:Kk | New medicine |
Non-Patent Citations (4)
| Title |
|---|
| JPN6012033638; 黄啓栄ら: 'ショウキョウのセロトニンによって誘発された体温降下及び下痢に対する作用' 薬学雑誌 Ｖｏｌ．１１０、Ｎｏ．１２, 1990, ｐ．９３６-９４２ * |
| JPN6012033639; 黄啓栄ら: 'ショウキョウの抗５-ＨＴ作用と作用成分' 和漢医薬学会誌 Ｖｏｌ．６、Ｎｏ．３, 1989, ｐ．３４４-３４５ * |
| JPN6012033641; 黄啓栄ら: 'ショウキョウの抗５-ＨＴ作用と作用成分' 和漢医薬学会誌 Ｖｏｌ．５、Ｎｏ．３, 1988, ｐ．３８６-３８７ * |
| JPN6012033643; 佐々木巖ら: '大建中湯の消化管運動亢進作用とその機序' Ｐｒｏｇ． Ｍｅｄ． Ｖｏｌ．２４, 2004, ｐ．１３８４-１３８７ * |
Cited By (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832717A (en) * | 2008-07-25 | 2016-08-10 | 爱默蕾大学 | Treatment of various disorders with 7,8-dihydroxyflavone and derivatives thereof |
| CN102143744B (en) * | 2008-07-25 | 2016-08-31 | 爱默蕾大学 | 7,8-dihydroxyflavone and derivant purposes in the medicine of preparation treatment depression thereof |
| EP2323649A4 (en) * | 2008-07-25 | 2011-09-07 | Univ Emory | Treating various disorders with 7,8-dihydroxyflavone and derivatives thereof |
| CN102215857A (en) * | 2008-11-19 | 2011-10-12 | 庆熙大学校产学协力团 | Pharmaceutical composition containing ginger extract or shogaol |
| JP2012062261A (en) * | 2010-09-15 | 2012-03-29 | Maruzen Pharmaceut Co Ltd | Composition for improving mood disorders |
| JP2013071928A (en) * | 2011-09-29 | 2013-04-22 | Yoshiko Furukawa | Composition for treatment of cranial nerve disease, prevention of cranial nerve disease or improvement in brain function |
| KR101369882B1 (en) * | 2012-01-17 | 2014-03-26 | 한국화학연구원 | Pharmaceutical composition for the prevention or treatment of asthma comprising (4-hydroxy-3-methoxyphenyl)butenone derivative or a pharmaceutically acceptable salt thereof as an active ingredient |
| CN102552242A (en) * | 2012-01-18 | 2012-07-11 | 李康 | Application of nobiletin to preparation of medicament for treating allelgic asthma |
| US20170029399A1 (en) * | 2014-01-28 | 2017-02-02 | Virginia Commonwealth University | 2-substituted-5-hydroxy-4h-chromen-4-ones as novel ligands for the serotonin receptor 2b (5-ht2b) |
| US9884836B2 (en) * | 2014-01-28 | 2018-02-06 | Virginia Commonwealth University | 2-substituted-5-hydroxy-4H-chromen-4-ones as novel ligands for the serotonin receptor 2B (5-HT2B) |
| WO2016016153A1 (en) * | 2014-07-30 | 2016-02-04 | Symrise Ag | Hydroxyflavanones as appetite stimulants |
| EP2990036A1 (en) * | 2014-07-30 | 2016-03-02 | Symrise AG | Hydroxyflavones for stimulating appetite |
| US20170135982A1 (en) * | 2014-07-30 | 2017-05-18 | Symrise Ag | Hydroxyflavanones as Appetite Stimulants |
| US10561633B2 (en) | 2014-07-30 | 2020-02-18 | Symrise Ag | Hydroxyflavanones as appetite stimulants |
| JPWO2016075960A1 (en) * | 2014-11-12 | 2017-08-17 | 株式会社 沖縄リサーチセンター | Pharmaceutical composition for preventing or ameliorating urination disorder, antagonist for urination disorder-related receptor or method for preventing or ameliorating urination disorder using the pharmaceutical composition or antagonist |
| CN114984000A (en) * | 2022-06-14 | 2022-09-02 | 中国科学院昆明动物研究所 | Application of toddaline and/or glycycoumarin in preparing medicine for improving resistance to pain |
| CN114984000B (en) * | 2022-06-14 | 2023-08-08 | 中国科学院昆明动物研究所 | Application of toddaline and/or glycyrrhizin in preparation of medicine for improving pain resistance |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2008156297A (en) | Serotonin 2b and/or 2c receptor antagonist | |
| WO1999064011A1 (en) | Drugs | |
| CN102395575A (en) | P38map kinase inhibitor | |
| JP2011157372A (en) | Method of treating functional bowel disorder | |
| WO2007147330A1 (en) | The application of the bakuchiol compounds | |
| HUT74949A (en) | Epibatidine and derivatives thereof as cholinergic receptor agonists and antagonists | |
| MXPA04012659A (en) | Use of mglur5 antagonists for the treatment of gerd. | |
| JP2017119702A (en) | Agent for preventing or treating neuropathic pain associated with guillain-barre syndrome | |
| CN109153672A (en) | TRPV4 antagonist | |
| JP5259181B2 (en) | Preventive or therapeutic agent for depression or anxiety | |
| CN108430475A (en) | Dimension difficult to understand for treating chronic cough is smooth | |
| JPH11501051A (en) | Medications intended to treat obsessive-compulsive disorder, sleep apnea, sexual dysfunction, vomiting and motion sickness | |
| KR20100126223A (en) | Composition for preventing or treating irritable bowel syndrome | |
| CN114555577A (en) | Thiophene derivatives for the treatment of portal vein inflammation and fibrosis | |
| WO2024016640A1 (en) | Antihistamine compound, and preparation method therefor and use thereof | |
| WO1999026612A1 (en) | Novel cannabinoid receptor modulators | |
| CN101982174A (en) | Formula of compound medicine preparation for relieving cough and preventing asthma and preparation method thereof | |
| CN102112469B (en) | Silent desensitizers of neuronal nAChR and methods of use thereof | |
| TWI289060B (en) | Pharmaceutical composition for improving the recovery of post-stroke patients | |
| US6333345B1 (en) | Methods of using and compositions comprising N-desmethylzolpidem | |
| JPH0352816A (en) | Remedy for nephritis | |
| JP4677191B2 (en) | Treatment for irritable bowel syndrome | |
| US7842702B2 (en) | Treatment for irritable bowel syndrome | |
| JP2004500333A (en) | Use of 2-amino-4- (4-fluoronaphth-1-yl) -6-isopropylpyrimidine in the treatment of gastrointestinal tract disorders | |
| KR101324689B1 (en) | Pharmaceutical composition comprising a 1-(3-chlorophenyl)-3-alkylpiperazine for treating apetite disorder |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20091127 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20091208 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20091208 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20120703 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20121113 |